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Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency.
Mol Ther. 2008 Mar; 16(3):590-8.MT

Abstract

Gene therapy for X-linked severe combined immunodeficiency (SCID-X1) has proven highly effective for long-term restoration of immunity in human subjects. However, the development of lymphoproliferative complications due to dysregulated proto-oncogene expression has underlined the necessity for developing safer vector systems. To reduce the potential for insertional mutagenesis, we have evaluated the efficacy of self-inactivating (SIN) gammaretroviral vectors in cellular and in vivo models of SCID-X1. Vectors incorporating an internal human elongation factor-1alpha regulatory element were capable of fully restoring the lymphoid differentiation potential of gammac-deficient lineage negative cells. Multilineage lymphoid reconstitution of a murine model was achieved at a similar level to that achieved by a conventional long-terminal repeat (LTR)-regulated vector used in previous clinical trials. Functional proliferative responses to mitogenic stimuli were also restored, and serum immunoglobulin levels were normalized. The reduced mutagenic potential conferred by SIN vector configurations and alternative non-LTR-based regulatory elements, together with proven efficacy in correction of cellular defects provides an important platform for development of the next phase of clinical trials for SCID-X1.

Authors+Show Affiliations

Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, University College London, London, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18180772

Citation

Thornhill, Susannah I., et al. "Self-inactivating Gammaretroviral Vectors for Gene Therapy of X-linked Severe Combined Immunodeficiency." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 16, no. 3, 2008, pp. 590-8.
Thornhill SI, Schambach A, Howe SJ, et al. Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency. Mol Ther. 2008;16(3):590-8.
Thornhill, S. I., Schambach, A., Howe, S. J., Ulaganathan, M., Grassman, E., Williams, D., Schiedlmeier, B., Sebire, N. J., Gaspar, H. B., Kinnon, C., Baum, C., & Thrasher, A. J. (2008). Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency. Molecular Therapy : the Journal of the American Society of Gene Therapy, 16(3), 590-8. https://doi.org/10.1038/sj.mt.6300393
Thornhill SI, et al. Self-inactivating Gammaretroviral Vectors for Gene Therapy of X-linked Severe Combined Immunodeficiency. Mol Ther. 2008;16(3):590-8. PubMed PMID: 18180772.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency. AU - Thornhill,Susannah I, AU - Schambach,Axel, AU - Howe,Steven J, AU - Ulaganathan,Meera, AU - Grassman,Elke, AU - Williams,David, AU - Schiedlmeier,Bernhard, AU - Sebire,Neil J, AU - Gaspar,H Bobby, AU - Kinnon,Christine, AU - Baum,Christopher, AU - Thrasher,Adrian J, Y1 - 2008/01/08/ PY - 2008/1/9/pubmed PY - 2008/7/26/medline PY - 2008/1/9/entrez SP - 590 EP - 8 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 16 IS - 3 N2 - Gene therapy for X-linked severe combined immunodeficiency (SCID-X1) has proven highly effective for long-term restoration of immunity in human subjects. However, the development of lymphoproliferative complications due to dysregulated proto-oncogene expression has underlined the necessity for developing safer vector systems. To reduce the potential for insertional mutagenesis, we have evaluated the efficacy of self-inactivating (SIN) gammaretroviral vectors in cellular and in vivo models of SCID-X1. Vectors incorporating an internal human elongation factor-1alpha regulatory element were capable of fully restoring the lymphoid differentiation potential of gammac-deficient lineage negative cells. Multilineage lymphoid reconstitution of a murine model was achieved at a similar level to that achieved by a conventional long-terminal repeat (LTR)-regulated vector used in previous clinical trials. Functional proliferative responses to mitogenic stimuli were also restored, and serum immunoglobulin levels were normalized. The reduced mutagenic potential conferred by SIN vector configurations and alternative non-LTR-based regulatory elements, together with proven efficacy in correction of cellular defects provides an important platform for development of the next phase of clinical trials for SCID-X1. SN - 1525-0024 UR - https://www.unboundmedicine.com/medline/citation/18180772/Self_inactivating_gammaretroviral_vectors_for_gene_therapy_of_X_linked_severe_combined_immunodeficiency_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(16)31434-4 DB - PRIME DP - Unbound Medicine ER -